Researchers Take Step Toward Synthetic Life

Taking a significant step toward the creation of
synthetic forms of life, researchers reported Thursday
that they had manufactured the entire genome of a
bacterium by stitching together its chemical components.

Scientists had previously constructed the complete
DNA of viruses, but this is the first time it has been
done for bacteria, which are far more complex. The
genome is more than 10 times as long as the longest
piece of DNA ever synthesized.

The feat is a watershed for the emerging field called
synthetic biology, which involves the design of
organisms to perform particular tasks, like making
biofuels. Synthetic biologists envision being able to
design an organism on a computer, press the “print”
button to have the necessary DNA made and then put that
DNA into a cell to produce a custom-made creature.

“What we are doing with the synthetic chromosome is
going to be the design process of the future,” said
Dr. J. Craig Venter, the boundary-pushing gene
scientist.

Dr. Venter assembled the team that made the bacterial
genome as part of his well-publicized quest to create
the first synthetic organism. The work was published
online Thursday by the journal Science.

But there are concerns that synthetic biology could
be used to make pathogens, or that errors by
well-intended scientists could produce organisms that
run amok. The genome of the
smallpox virus can in theory now be synthesized
using the techniques reported on Thursday since it is
only about one-third the size of the genome manufactured
by Dr. Venter’s group.

In any case, there are many hurdles to overcome
before Dr. Venter’s vision of “life by design” is
realized. The synthetic genome made by Dr. Venter’s team
was not designed from scratch, but rather was a copy,
with only a few changes, of the genetic sequence of a
natural bacterium called Mycoplasma genitalium.

Moreover, Dr. Venter’s team, led by a Nobel laureate,
Hamilton O. Smith, has yet to accomplish the next — and
biggest — step. That would be to insert the synthetic
chromosome into a living microbe and have it “boot up”
and take control of the organism’s functions.

If that happened, it would be considered by some to
be the creation of the first synthetic organism. The
failure to achieve that tempered the reaction of some
outside scientists to the announced achievement.

“Right now, all they’ve done is shown they can buy a
bunch of DNA and put it together,” said George M.
Church, a professor of
genetics at Harvard Medical School.

Dr. Venter’s team last year reported successfully
doing such a chromosome transplant, but it was with the
natural genome of one type of Mycoplasma transplanted
into another species of that bacterium.

Dr. Venter said in a telephone news conference
Thursday that each pair of donor genome and recipient
cell presented unique problems. The scientists also
think they interrupted the functioning of one crucial
gene, a correctable problem.

“It’s not a slam dunk or we would be announcing it
today,” Dr. Venter told reporters. Still, he said, “I
will be equally surprised and disappointed if we can’t
do it in 2008.”

The bacterial genome that was synthesized consisted
of 582,970 base pairs, the chemical units of the genetic
code represented by the letters A, C, G and T. The
longest stretch of synthetic DNA reported in a
scientific paper was about 32,000 bases long, though
some companies say they have made ones with about
50,000.

The machines that string bases together make many
errors, so it is impractical to make a string of more
than 50 to 100 bases at once. But some companies — the
foundries of the biotechnology era — now make genes
thousands of bases long by splicing the shorter strings.

The Venter team ordered 101 such sequences, each
5,000 to 7,000 bases long, from these companies. It then
joined them into ever-bigger pieces. Finally, four big
pieces were put into yeast, which hooked them together
using a natural gene repair mechanism.

The process was started in late 2002, Dr. Venter
said, and cost millions of dollars. That led some
scientists to question why someone would want to
synthesize an entire organism when existing organisms
can be modified through genetic engineering.

“To some extent, it’s something that was driven by ‘I
want to be the first person to do it,’ ” surmised Jeremy
Minshull, chief executive of DNA 2.0, a company that
supplied some of the DNA stretches to the Venter team.

Dr. Minshull said that scientists did not yet know
enough about how living things work to design an entire
genome. “Our synthetic capability way outpaces our
understanding of what we want to do,” he said.

For now, that is the case, Dr. Venter concedes. He
runs a company, Synthetic Genomics, that is using
genetic engineering to produce biofuels. But he and
other scientists say that DNA synthesis is following the
path of computer chips, with capability rising rapidly
and costs — now about $1 per base — falling swiftly. At
some point, they say, it will become faster and cheaper
for scientists to synthesize an organism from scratch
rather than cut and paste genes from one organism to
another.

The ability to synthesize genomes would allow for
more scientific experimentation. Dr. Venter said he
would now be able to create organisms missing dozens of
genes to answer the initial question that inspired the
research in 1995: What is the minimum set of genes
needed for life?

Dr. Venter, who runs the nonprofit J. Craig Venter
Institute in Rockville, Md., is most known for
sequencing the human genome in a race with the publicly
financed Human Genome Project.

Some activist groups say that Dr. Venter is going too
far, too fast, this time, and that synthetic biology
needs outside regulation to prevent the introduction of
dangerous organisms, created by evil intent or by
innocent error.

“The fact that he’s pushing ahead with this without
any societal oversight is very worrying,” said Jim
Thomas, a program manager at the ETC Group, a technology
watchdog group based in Canada. He also said it was
worrisome that Dr. Venter was applying for very broad
patents in synthetic biology.

Dr. Venter said that the field had discussed ethics
and safety since it started and that his work had been
reviewed by ethicists.

In the new genome, he said, one gene was changed to
make any resulting organism noninfective. (Mycoplasma
genitalium, which can be transmitted sexually, is
associated with inflammation.)

The team also added some DNA segments to serve as
“watermarks,” allowing scientists to distinguish the
synthetic genome from the natural one.

These watermarks, Dr. Venter noted, contain coded
messages. Sleuths would have to determine the amino acid
sequence coded for by the watermarks to decipher the
message.